Despite liver and kidney utilization rates in the 80-90% range, the donor lung utilization rate for transplantation in the United States is approximately 20%, and the demand for donor lungs far exceeds the supply. This donor lung shortage leads to long waiting times for lung transplantation and a high mortality in patients awaiting lung transplantation. The most common reason for failure to utilize donor lungs for transplantation is donor hypoxemia and pulmonary infiltrates. Although brain dead organ donors are universally mechanically ventilated, the potential contribution of the mode of mechanical ventilation to donor lung dysfunction has not been adequately studied and the choice of ventilator settings during management of the brain dead organ donor is largely empiric. In our recently completed randomized clinical trial of nebulized albuterol versus placebo in 506 organ donors, the extent of radiographic lung atelectasis was a major predictor of poor donor oxygenation and lower rates of lung utilization. An open lung protective ventilator (OLPV) that aims to reduce atelectasis by maximizing lung recruitment while minimizing lung injury has improved outcomes in other clinical settings including patients with and at risk for acute lung injury and in a small study in European organ donors. However, most U.S. organ donors are still ventilated with a conventional ventilation strategy with low levels of positive end-expiratory pressure (PEEP) and higher tidal volumes. Therefore, we propose to prospectively test the hypothesis that ventilation of organ donors with an OLPV strategy during the donor management period will improve donor lung utilization and oxygenation compared to a conventional higher tidal volume and lower PEEP strategy and to investigate the cellular and molecular mechanisms of human ventilator-associated lung injury. In Aim 1, we will test the effect of an OLPV strategy compared to a conventional ventilator strategy on donor lung utilization, donor oxygenation, atelectasis and recipient outcomes in a randomized clinical trial i 400 donors managed by the California Transplant Donor Network. In translational studies in Aim 2, we will test the effect of an OLPV strategy on lung injury in the excised human lung as measured by (1) alveolar- capillary barrier permeability to protein, (2) the extent of pulmonary edema, (3) histologic grading and (4) also determine whether the protective effects of OLPV are mediated through reductions in lung epithelial injury and apoptosis. Completion of the clinical trial in Aim 1 will have a high impact, providing significant new information that could transform donor management in the United States and lead to increased rates of donor lung utilization, decreased wait times for lung transplantation, and reduced mortality while awaiting lung transplantation. The proposed studies build on the comprehensive and unique infrastructure for donor clinical trials that our team of investigators has developed in collaboration with the California Transplant Donor Network. The proposed studies in Aim 2 will further enhance the impact of the proposed studies by studying the mechanisms of the protective effect of OLPV in large numbers of excised human lungs, a novel resource.